Current antitumor vaccine strategies based on either whole tumor-cells or antigen-specific targets for the treatment of many cancers tend to focus primarily on the cellular arm of the immune response especially the elicitation of cytotoxic T-cells (CTL's). Other immunotherapeutic strategies have widely relied on passive administration of antitumor monoclonal antibodies such as Herceptin. A number of HER-2 clinical trials have already been conducted and in general, although such vaccination strategies are safe, there are a number of concerns associated with both strategies. However, the optimal design, formulation and composition of future cancer vaccines have yet to be determined and clinical responses, especially in conjunction with vaccine immune responses, are still scarce. Renewed interest in developing vaccines for use in cancer treatment stems from a better understanding of the immune system and tumor escape mechanisms. The challenge to the design of effective immune-based strategies for cancer relies on the ability to stimulate both strong cellular and/or humoral anti-tumor immune responses. This proposal constitutes a unique approach to cancer immunotherapy to develop a multi-epitope based vaccine with enhanced anti-tumor antibody responses. The current proposal directly follows work completed in the past year following a series of original and basic observations and a hypothesis-driven in vitro and in vivo animal studies to conduct new human clinical trials with novel chimeric and multi-epitope vaccine candidates. Briefly, we have developed a combination approach targeting three B cell epitope of the extracellular domain of HER-2. Antibodies elicited by a combination of two epitopes mediated superior tumor cell binding, tumor cell growth inhibition of two human breast tumor cell lines SKBR3 and BT474 both in vitro and in vivo and HER-2 receptor endocytosis than either the individual immunogens. These studies demonstrate the potential of multi-epitope peptide vaccine for human cancer therapy. Thus, the immediate specific aims of the proposal are: Specific Aim 1: To determine the maximum tolerable dose (MTD) of combination vaccine and characterize the clinical toxicity of immunization. Specific Aim 2:To determine whether both humoral and cellular immune responses are elicited in patients immunized with combination vaccines and nor-MDP as adjuvant and to study the underlying mechanisms of anti-tumor activity in vitro and in vivo.